Identification of Novel Influenza Inhibitors

描述（由申请人提供）：流感病毒是全球公共卫生关注的C类生物防御病原体，因为它每年导致300万至500万例严重疾病，并且因为可能出现新的高致病性菌株，可能导致大流行疾病。迄今为止，只有两种成功开发的流感药物靶点和四种获批的药物。M2 H+离子通道已被证明是病毒感染的必要条件，抑制其活性是一种有效的抗病毒策略。金刚烷胺和金刚乙胺这两种化合物抑制M2，在过去的40年里一直被用作流感治疗药物。然而，许多目前流行的流感毒株现在对它们表现出耐药性。因此，通过新的相互作用机制抑制M2的新药具有作为流感治疗药物的巨大潜力。然而，研究离子通道活性的传统方法不适合用于鉴定新抑制剂的高通量筛选技术。到目前为止，这在很大程度上阻碍了新型M2抑制剂的开发。Integral Molecular专注于开发新的策略来操纵和研究整体膜蛋白，包括离子通道。我们已经开发了一种监测M2活性的新技术，我们已经证明该技术非常适合高通量筛选（HTS）应用。在成功开发了适合M2筛选的HTS分析后，目前的应用建议使用它来识别和开发新的M2抑制剂。公共卫生相关性：SBIR将产生的产品是一种新型流感小分子抑制剂。本提案中开发的抑制剂将针对经过验证的流感分子靶点M2，并克服金刚烷类药物面临的主要障碍，因为化合物将对许多M2变体进行效力筛选，以最大限度地提高开发广谱流感抑制剂的机会。M2对流感生命周期至关重要，这表明下一代M2活性抑制剂具有巨大的治疗潜力。

DESCRIPTION (provided by applicant): Influenza virus is a Category C biodefense pathogen of global public health concern because it causes 3-5 million cases of severe illness every year, and because of the potential for the emergence of new, highly pathogenic strains that could cause pandemic disease. To date, there have been only two successfully-exploited influenza drug targets and only four approved drugs. The M2 H+ ion channel has been shown to be necessary for viral infectivity, and suppression of its activity is a well validated anti-viral strategy. The compounds amantadine and rimantadine inhibit M2 and have been used as influenza therapeutics for the past 40 years. However, many currently circulating influenza strains now exhibit resistance to them. New drugs that inhibit M2 via novel mechanisms of interaction therefore have significant potential as influenza therapeutics. However, conventional methods for studying the activity of ion channels are poorly suited to high-throughput screening techniques for identifying new inhibitors. Until now, this has largely precluded the development of new classes of M2 inhibitors. Integral Molecular specializes in developing novel strategies for manipulating and studying integral membrane proteins, including ion channels. We have developed a novel technology for monitoring the activity of M2 that we have shown to be well-suited to high-throughput screening (HTS) applications. Having successfully developed a suitable HTS assay for M2 screening, the current application proposes to use it to identify and develop novel M2 inhibitors. PUBLIC HEALTH RELEVANCE: The product that will result from this SBIR is a novel small molecule inhibitor of influenza. The inhibitors developed in this proposal will target a validated influenza molecular target, M2, and overcome the major obstacles faced by the adamantane drugs because compounds will be screened for potency against a number of M2 variants to maximize the chances of developing a broad-spectrum influenza inhibitor. M2 is critical to the influenza life-cycle, suggesting there is substantial therapeutic potential for next-generation inhibitors of M2 activity.